Endothelial dysfunction is common in acute and chronic organ injury. Isoflurane is a widely used halogenated volatile anesthetic during the perioperative period and protects against endothelial cell ...death and inflammation. In this study, we tested whether isoflurane induces endothelial ecto-5'-nucleotidase (CD73) and cytoprotective adenosine generation to protect against endothelial cell injury. Clinically relevant concentrations of isoflurane induced CD73 activity and increased adenosine generation in cultured human umbilical vein or mouse glomerular endothelial cells. Surprisingly, isoflurane-mediated induction of endothelial CD73 activity occurred within 1 hr and without synthesizing new CD73. We determined that isoflurane rapidly increased CD73 containing endothelial microparticles into the cell culture media. Indeed, microparticles isolated from isoflurane-treated endothelial cells had significantly higher CD73 activity as well as increased CD73 protein. In vivo, plasma from mice anesthetized with isoflurane had significantly higher endothelial cell-derived CD144+ CD73+ microparticles and had increased microparticle CD73 activity compared to plasma from pentobarbital-anesthetized mice. Supporting a critical role of CD73 in isoflurane-mediated endothelial protection, a selective CD73 inhibitor (APCP) prevented isoflurane-induced protection against human endothelial cell inflammation and apoptosis. In addition, isoflurane activated endothelial cells Rho kinase evidenced by myosin phosphatase target subunit-1 and myosin light chain phosphorylation. Furthermore, isoflurane-induced release of CD73 containing microparticles was significantly attenuated by a selective Rho kinase inhibitor (Y27632). Taken together, we conclude that the volatile anesthetic isoflurane causes Rho kinase-mediated release of endothelial microparticles containing preformed CD73 and increase adenosine generation to protect against endothelial apoptosis and inflammation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of the present study was to evaluate the protective effect of palmatine, one of active ingredients of
Coptidis rhizoma, against myocardial ischemia–reperfusion (I/R) injury is due to its ...antioxidant and anti-inflammatory action. Adult male rats were subjected to 30
min of ischemia and 6 or 24
h of reperfusion. Rats were randomized to receive vehicle or palmatine 1
h before reperfusion. Infarct size, myocardial function, and the antioxidant enzyme activity, such as malonaldehyde (MDA), lactate dehydrogenase (LDH), creatine phosphokinase (CK), superoxide dismutase (SOD) and catalase (CAT) were measured. Palmatine significantly improved I/R-induced myocardial dysfunction by increasing the values of the first derivative (±dp/dt) of left ventricular pressure and decreased infarct size by 50% (
P
<
0.01 versus vehicle). As expected, palmatine markedly inhibited the increase of LDH, CK, and MDA contents in I/R rat serum, and it also significantly inhibited the decline of the activity of SOD and CAT in I/R cardiac tissues. In addition, COX-2 and iNOS expression in I/R myocardium was significantly reduced. Interestingly, plamatine increased heme oxygenase (HO)-1 induction in human aortic endothelial cells. We concluded that palmatine protects hearts from I/R injury in rats possibly by reducing oxidative stress and modulating inflammatory mediators.
Persistent non-specific low back pain (PNSLBP) is one of the most frequently experienced types of back pain around the world. Wet-cupping is a common intervention for various pain conditions, ...especially in Korea. In this context, we conducted a pilot study to determine the effectiveness and safety of wet-cupping treatment for PNSLBP.
We recruited 32 participants (21 in the wet-cupping group and 11 in the waiting-list group) who had been having PNSLBP for at least 3 months. The participants were recruited at the clinical research centre of the Korea Institute of Oriental Medicine, Korea. Eligible participants were randomly allocated to wet-cupping and waiting-list groups. Following the practice of traditional Korean medicine, the treatment group was provided with wet-cupping treatment at two acupuncture points among the BL23, BL24 and BL25 6 times within 2 weeks. Usual care, including providing brochures for exercise, general advice for PNSLBP and acetaminophen, was allowed in both groups. Separate assessors participated in the outcome assessment. We used the 0 to 100 numerical rating scale (NRS) for pain, the McGill Pain Questionnaire for pain intensity (PPI) and the Oswestry Disability Questionnaire (ODQ), and we assessed acetaminophen use and safety issues.
The results showed that the NRS score for pain decreased (-16.0 95% CI: -24.4 to -7.7 in the wet-cupping group and -9.1 -18.1 to -0.1 in the waiting-list group), but there was no statistical difference between the groups (p = 0.52). However, the PPI scores showed significant differences between the two groups (-1.2 -1.6 to -0.8 for the wet-cupping group and -0.2 -0.8 to 0.4 for the waiting-list group, p < 0.01). In addition, less acetaminophen was used in the wet-cupping group during 4 weeks (p = 0.09). The ODQ score did not show significant differences between the two groups (-5.60 -8.90 to -2.30 in the wet-cupping group and -1.8 -5.8 to 2.2 in the waiting-list group, p = 0.14). There was no report of adverse events due to wet-cupping.
This pilot study may provide preliminary data on the effectiveness and safety of wet-cupping treatments for PNSLBP. Future full-scale randomised controlled trials will be needed to provide firm evidence of the effectiveness of this intervention.
Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein ...cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.
The objective of this study is to evaluate the preoperative hematological parameters to predict ovarian torsion in patients with ovarian mature cystic teratoma. We also analyzed the diagnostic value ...of these makers to predict ovarian necrosis in cases of torsion as well as the effect of torsion on ovarian reserve.
This is a retrospective study of 132 patients who received either laparoscopic or laparotomy surgery for OMCT at a single university hospital. Clinical characteristics and preoperative hematological parameters were compared between patients with or without torsion. Patients with torsion were further classified as infarction and non-infarction group. Preoperative parameters were compared between the two groups as well.
White blood cell (WBC) count, neutrophil percent, neutrophil count, and neutrophil to lymphocyte ratio (NLR) were higher in the torsion group (n=37) than the non-torsion group (n=95) (
<0.05 for all). Although statistically insignificant, the preoperative anti-Mullerian hormone (AMH) was lower in the torsion group than the non-torsion group (4.07 ± 3.38 vs 6.1 ± 3.6,
=0.122). In cases of torsion, the infarction group showed higher WBC count and lymphocyte count but lower hemoglobin level and platelet to lymphocyte ratio (PLR) than the non-infarction group (
<0.05 for all).
The WBC count, neutrophil percent, neutrophil count, and NLR were higher in the cases of OMCT with torsion, and these parameters may be useful to diagnose OMCT with torsion. Also, adnexal torsion may deteriorate ovarian reserved as indicated by decreased AMH in torsion group.
Although hepatitis B virus X protein (HBx) has been implicated in abnormal lipid metabolism in hepatitis B virus (HBV)–associated hepatic steatosis, its underlying molecular mechanism remains ...unclear. Liver X receptor (LXR) plays an important role in regulating the expression of genes involved in hepatic lipogenesis. Here we demonstrate that LXRα and LXRβ mediate HBV‐associated hepatic steatosis. We have found that HBx induces the expression of LXR and its lipogenic target genes, such as sterol regulatory element binding protein‐1c (SREBP‐1c), fatty acid synthase (FAS), and peroxisome proliferator‐activated receptor, and this is accompanied by the accumulation of lipid droplets. RNA interference with LXR expression decreases the amount of lipid droplets as well as the expression of the lipogenic genes, and this indicates that HBx‐induced lipogenesis is LXR‐dependent. LXRα and HBx colocalize in the nucleus and are physically associated. HBx induces the transactivation function of LXRα by recruiting CREB binding protein to the promoter of the target gene. Furthermore, we have observed that expression of LXR is increased in the livers of HBx‐transgenic mice. Finally, there is a significant increase in the expression of LXRβ (P = 0.036), SREBP‐1c (P = 0.008), FAS, and stearoyl–coenyzme A desaturase‐1 (P = 0.001) in hepatocellular carcinoma (HCC) in comparison with adjacent nontumorous nodules in human HBV‐associated HCC specimens. Conclusion: Our results suggest a novel association between HBx and LXR that may represent an important mechanism explaining HBx‐induced hepatic lipogenesis during HBV‐associated hepatic carcinogenesis. (HEPATOLOGY 2009.)
Chamaecyparis obtusa has been traditionally used as an antibiotic agent and in cosmetics for the prevention of microorganism infection and skin troubles. Atopic dermatitis (AD) is a chronic ...inflammatory skin disease that encompasses immunologic responses, susceptibility factors and compromised skin-barrier function. Use of plant medicines in therapeutic treatment of AD has recently been suggested as an alternative therapeutic option. The present study examined the effect of elemol, an active component of Chamaecyparis obtusa, on AD using in vivo and in vitro models. RBL-2H3 cells were stimulated with concanavalin A and dinitrophenyl human serum albumin, and atopic dermatitis was induced in BALB/c mice by topical application of 2,4-dinitrochlorobenzene (DNCB) prior to elemol treatment. The mRNA expression was evaluated by reverse transcription quantitative polymerase chain reaction, and the levels of β-hexosaminidase and serum immunoglobulin E (IgE) were examined by ELISA. Histological changes were also performed by microscopy. Elemol attenuated the onset of AD-like skin lesions, reduced serum IgE levels and decreased mast cell infiltration into the dermis and hypodermis. In addition, elemol downregulated the transcriptional expression of several pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 and IκBα, in the skin of the DNCB-induced animal models of AD. In the RBL-2H3 mast cell line, elemol significantly inhibited the mRNA expression of IL-4 and IL-13, and further attenuated the release of β-hexosaminidase from mast cells. Histological examination revealed that elemol significantly ameliorated the DNCB-induced dermal destruction in mice. The results of the present study suggested that elemol may have therapeutic potential in the treatment of AD due to its immunosuppressive effects.
To investigate CT colonography (CTC) performance for detecting and characterising synchronous lesions proximal to a stenosing colorectal cancer and to suggest patient management strategies according ...to the CTC findings.
411 consecutive patients underwent CTC for proximal colonic evaluation after failed colonoscopy past a newly diagnosed stenosing colorectal cancer. Pathological examination of colectomy specimen and/or postsurgical colonoscopy with pathological confirmation of the proximal synchronous lesions to serve as reference standards existed in 284 patients. Per-patient and per-lesion diagnostic performance measures of CTC for diagnosing proximal synchronous lesions ≥6 mm analysed by histopathological categories were obtained for the 284 patients. Per-lesion sensitivity and positive predictive value (PPV) of various CTC lesion size criteria and lesion size combined with other CTC findings for diagnosing cancer in the proximal colon were determined.
Both per-patient and per-lesion CTC detection sensitivities for proximal synchronous cancers were 100% (6/6 patients and 8/8 lesions; 95% CI 64.3% to 100% and 70.7% to 100%, respectively) with the corresponding per-patient negative predictive value (NPV) of a negative CTC of 100% (194/194 patients; 95% CI 98.3% to 100%). Per-patient NPV of a negative CTC for advanced neoplasia (ie, advanced adenomas and colorectal cancers) was 97.4% (189/194 patients; 95% CI 93.9% to 99.1%). A lesion size ≥15 mm on CTC as the criterion to specifically diagnose proximal cancer yielded 87.5% (7/8 lesions; 95% CI 50.8% to 99.9%) per-lesion sensitivity, rendering one 8-mm submucosal cancer mischaracterised as a non-cancerous lesion, and 70% (7/10 lesions; 95% CI 39.2% to 89.7%) per-lesion PPV. Additional CTC findings did not improve the sensitivity.
CTC is highly sensitive in detecting synchronous cancers proximal to a stenosing colorectal cancer. CTC has limited capability in differentiating advanced adenomas from colorectal cancer and this compromises the PPV of CTC for the presence of proximal cancer.
NO, produced from L-arginine in a reaction catalyzed by NO synthase, is an endogenous free radical with multiple functions in mammalian cells. Here, we demonstrate that endogenously produced NO can ...suppress c-Jun N-terminal kinase (JNK) activation in intact cells. Treatment of BV-2 murine microglial cells with IFN-γ induced endogenous NO production, concomitantly suppressing JNK1 activation. Similarly, IFN-γ induced suppression of JNK1 activation in RAW264.7 murine macrophage cells and rat alveolar macrophages. The IFN-γ-induced suppression of JNK1 activation in BV-2, RAW264.7, or rat alveolar macrophage cells was completely prevented by NG-nitro-L-arginine, a NO synthase inhibitor. Interestingly, the IFN-γ-induced suppression of JNK1 activation was not affected by 1H-1,2,4oxadiazolo4,3-aquinoxalin-1-one, an inhibitor of guanylyl cyclase. 8-Bromo-cGMP, amembrane-permeant analogue of cGMP, did not change JNK1 activation in intact cells either. In contrast, S-nitro-N-acetyl-DL-penicillamine (SNAP), a NO donor, inhibited JNK1 activity in vitro. Furthermore, a thiol reducing agent, DTT, reversed not only the in vitro inhibition of JNK1 activity by SNAP but also the in vivo suppression of JNK1 activity by IFN-γ. Substitution of serine for cysteine-116 in JNK1 abolished the inhibitory effect of IFN-γ or SNAP on JNK1 activity in vivo or in vitro, respectively. Moreover, IFN-γ enhanced endogenous S-nitrosylation of JNK1 in RAW264.7 cells. Collectively, our data suggest that endogenous NO mediates the IFN-γ-induced suppression of JNK1 activation in macrophage cells by means of a thiol-redox mechanism.
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